A scoping review protocol on diagnostic strategies to detect occult malignancies in individuals with ischemic stroke

Background Emerging data show an increased risk of ischemic stroke in patients with a new diagnosis of cancer. As the risk of stroke begins to increase 150 days before cancer is diagnosed, stroke may be the first clinical manifestation of undiagnosed cancer. About 6% of patients with cryptogenic ischemic stroke (unknown etiology after diagnostic evaluations) are diagnosed with cancer within one year. However, the optimal cancer screening strategy in this population is not known. We aim to conduct a scoping review of screening strategies for occult cancer in individuals with ischemic stroke. Methods Electronic databases including MEDLINE (Ovid), EMBASE (Ovid), CINAHL (EBSCOhost) and Scopus will be systematically searched to identify articles that report on screening strategies for occult cancer in individuals with ischemic stroke. At least two investigators will independently perform two-stage study selection consisting of title/abstract screening and full-text review, followed by data extraction. Thereafter, a thematic analysis will be conducted to provide an overview of what diagnostic tests/strategies have been used, and their clinical utility in terms of positive and negative predictive value (when available). Conclusion We anticipate that the findings of this scoping review will identify strategies used to detect occult cancer in individuals with ischemic stroke and summarize their clinical utility (if reported). Addressing this knowledge gap will help guide the development of future clinical trials on occult cancer screening patients with ischemic stroke.


Methods
Electronic databases including MEDLINE (Ovid), EMBASE (Ovid), CINAHL (EBSCOhost) and Scopus will be systematically searched to identify articles that report on screening strategies for occult cancer in individuals with ischemic stroke. At least two investigators will independently perform two-stage study selection consisting of title/abstract screening and full-text review, followed by data extraction. Thereafter, a thematic analysis will be conducted to provide an overview of what diagnostic tests/strategies have been used, and their clinical utility in terms of positive and negative predictive value (when available).

Conclusion
We anticipate that the findings of this scoping review will identify strategies used to detect occult cancer in individuals with ischemic stroke and summarize their clinical utility (if reported). Addressing this knowledge gap will help guide the development of future clinical trials on occult cancer screening patients with ischemic stroke. This is a Registered Report and may have an associated publication; please check the article page on the journal site for any related articles.

Introduction
Ischemic stroke is a leading cause of disability and mortality worldwide, affecting millions of people [1,2]. Determining stroke etiology is key for optimal secondary stroke prevention, but remains unidentified in 10% to 40% of patients even after modern diagnostic workup (so-called cryptogenic stroke) [3,4]. The current definition of cryptogenic stroke is based on the definition used in the trial of ORG 10172 in Acute Stroke Treatment (TOAST) [5]. Cryptogenic stroke (or "stroke of undetermined etiology" in TOAST terminology) is defined as an ischemic brain infarction not attributable to large-artery atherosclerosis, small artery disease, or cardioembolism despite a standard vascular, cardiac, and serologic evaluation (Table 1). Emerging data suggest that active cancer is an important underlying cause of ischemic stroke in individuals with cryptogenic stroke, with unique pathophysiology and treatment considerations [6]. Several large studies have demonstrated an increased risk of ischemic stroke in patients with new cancer diagnoses compared to matched controls [7,8]. It is also increasingly recognized that stroke can precede cancer diagnosis by several months indicating that stroke may be the first manifestation of underlying cancer [9,10]. Up to 10% of individuals with cryptogenic ischemic stroke are diagnosed with cancer within one year, which is similar to the incidence of occult cancer in individuals with unprovoked (no identifiable major risk factors) thromboembolism (VTE) [10][11][12]. However, compared to the extensive literature on cancer associated VTE, research on cancer associated stroke is more limited [11]. Although experts endorse consideration of underlying occult cancer as an etiology of cryptogenic stroke [6,13,14], specific recommendations are lacking and no advice is given in current guidelines [15][16][17][18][19][20]. Given the uncertainty about the extent and type of existing literature regarding screening for occult cancer in patients with ischemic stroke, we will map the available evidence in this scoping review in order to identify current knowledge gaps prior to undertaking a systematic review.

Methods
This scoping review will be conducted according to the methodology proposed by Arksey and O'Malley [21,22] which consists of nine stages as follows: 1) identify the research question(s); 2) develop the inclusion criteria; 3) describe the planned approach to evidence searching, selection, data extraction, and presentation; 4) search for the evidence; 5) select the evidence; 6) extract the evidence; 7) analyze the evidence; 8) present the results; 9) summarize the evidence in relation to the purpose of the review, making conclusions and noting any implications of the findings. This study is registered with the Open Science Framework (https://osf.io/3h95q). The results will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR).

Research question
In patients with cryptogenic ischemic stroke, have occult cancer screening strategies been evaluated and, if so, what tests have been used and what is the clinical value in terms of positive and negative predictive value?

Inclusion and exclusion criteria
All articles that describe strategies for detecting occult cancers in adult patients with ischemic stroke (including, but not limited to, imaging tests, laboratory investigations, clinical assessments) will be assessed. Eligible articles include expert opinions, guidelines, narrative and systematic reviews, case-series and case-reports, conference abstracts, observational and randomized studies. Non-English reports, animal studies, studies limited to intracerebral hemorrhage, studies in patients with known cancers, studies on cardioembolic ischemic stroke (including fibroelastoma, atrial myxoma, and non-bacterial thrombotic endocarditis), and studies without details about screening strategies will be excluded. The reference lists of articles selected for full-text review will also be reviewed for potentially eligible studies that were not captured by the search.

Search strategy and information sources
The search strategy was developed by a health sciences librarian (VL) and peer-reviewed by an independent health sciences librarian from the University of Ottawa (Tables 2-5) [23]. MED-LINE (Ovid), Embase (Ovid), CINAHL (EBSCO), and Scopus were searched with no limits to language or publication date using appropriate subject headings and keywords (see S1 Checklist for full search details). The main search concepts comprise of terms related to ischemic stroke and cancer screening. Search results were exported to Covidence (Melbourne, Australia) and duplicates were eliminated using the platform's duplicate identification feature.

Article selection
We will use a two-stage study selection of title and abstract screening, followed by full-text review, to be completed by two independent reviewers [24]. Disagreements will be resolved by discussion, or involvement of a third reviewer if consensus cannot be reached. A PRISMA flow diagram will be used to summarize the process of article selection.

Data extraction and management
For studies that meet the inclusion criteria, relevant data will be extracted and captured using a standardized data extraction form. Specific data to be collected are shown in Table 6.

Conclusion
The objective of the scoping review described in this protocol is to summarize the available evidence on screening strategies to detect occult cancer in individuals with ischemic stroke. We anticipate that this review will summarize the type of tests and/or strategies that are used in clinical practice and provide preliminary evidence about their utility, but there will be heterogeneity due to existing knowledge gaps about the optimal strategy. Information gathered from this review will also help to guide the development of future clinical trials on screening strategies for occult cancer in individuals with ischemic stroke.